ZA200602031B - Antimalarial compositions and process thereof - Google Patents
Antimalarial compositions and process thereof Download PDFInfo
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- ZA200602031B ZA200602031B ZA200602031A ZA200602031A ZA200602031B ZA 200602031 B ZA200602031 B ZA 200602031B ZA 200602031 A ZA200602031 A ZA 200602031A ZA 200602031 A ZA200602031 A ZA 200602031A ZA 200602031 B ZA200602031 B ZA 200602031B
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- South Africa
- Prior art keywords
- derivative
- salt
- quinoline
- formulation according
- pharmaceutical product
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 14
- 239000000203 mixture Substances 0.000 title claims description 13
- 230000008569 process Effects 0.000 title claims description 10
- 239000003430 antimalarial agent Substances 0.000 title description 15
- 230000000078 anti-malarial effect Effects 0.000 title description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 38
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 claims description 21
- 238000009472 formulation Methods 0.000 claims description 20
- 229960004191 artemisinin Drugs 0.000 claims description 18
- 229930101531 artemisinin Natural products 0.000 claims description 18
- 201000004792 malaria Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical group C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims description 14
- 229960004991 artesunate Drugs 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 claims description 7
- 229960001444 amodiaquine Drugs 0.000 claims description 6
- 229960002521 artenimol Drugs 0.000 claims description 6
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 5
- 229960000981 artemether Drugs 0.000 claims description 5
- 229960003677 chloroquine Drugs 0.000 claims description 5
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 5
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 claims description 5
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 4
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims description 4
- -1 artesthesr Chemical compound 0.000 claims description 4
- 229930016266 dihydroartemisinin Natural products 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229960001962 mefloquine Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- BLUAFEHZUWYNDE-XRNKLDBLSA-N chembl77 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4C31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-XRNKLDBLSA-N 0.000 claims description 2
- 229960005179 primaquine Drugs 0.000 claims description 2
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 17
- 229940127557 pharmaceutical product Drugs 0.000 claims 17
- 239000000314 lubricant Substances 0.000 claims 6
- 239000003085 diluting agent Substances 0.000 claims 5
- 239000007884 disintegrant Substances 0.000 claims 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 3
- 239000011230 binding agent Substances 0.000 claims 3
- 239000002775 capsule Substances 0.000 claims 3
- 239000008101 lactose Substances 0.000 claims 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- 229920002472 Starch Polymers 0.000 claims 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000000194 fatty acid Substances 0.000 claims 2
- 229930195729 fatty acid Natural products 0.000 claims 2
- 150000004665 fatty acids Chemical class 0.000 claims 2
- 239000008187 granular material Substances 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 229940080313 sodium starch Drugs 0.000 claims 2
- 229940032147 starch Drugs 0.000 claims 2
- 235000019698 starch Nutrition 0.000 claims 2
- 239000008107 starch Substances 0.000 claims 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
- 229920002785 Croscarmellose sodium Polymers 0.000 claims 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims 1
- 241000237858 Gastropoda Species 0.000 claims 1
- 241001649123 Hemisus Species 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims 1
- 229930195725 Mannitol Natural products 0.000 claims 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims 1
- 229920000881 Modified starch Polymers 0.000 claims 1
- 241000430093 Proeces Species 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 229960000992 amodiaquine hydrochloride Drugs 0.000 claims 1
- 239000001506 calcium phosphate Substances 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 235000010980 cellulose Nutrition 0.000 claims 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims 1
- 229940038472 dicalcium phosphate Drugs 0.000 claims 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims 1
- 238000007907 direct compression Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims 1
- 239000000594 mannitol Substances 0.000 claims 1
- 235000010355 mannitol Nutrition 0.000 claims 1
- 229940016286 microcrystalline cellulose Drugs 0.000 claims 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims 1
- 239000008108 microcrystalline cellulose Substances 0.000 claims 1
- 238000003801 milling Methods 0.000 claims 1
- 239000002480 mineral oil Chemical class 0.000 claims 1
- 235000010446 mineral oil Nutrition 0.000 claims 1
- 229940126701 oral medication Drugs 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 235000015112 vegetable and seed oil Nutrition 0.000 claims 1
- 239000008158 vegetable oil Substances 0.000 claims 1
- 238000005550 wet granulation Methods 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 229940079593 drug Drugs 0.000 description 10
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 6
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- 229940033495 antimalarials Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 235000001405 Artemisia annua Nutrition 0.000 description 3
- 240000000011 Artemisia annua Species 0.000 description 3
- 208000030852 Parasitic disease Diseases 0.000 description 3
- 241000224016 Plasmodium Species 0.000 description 3
- 241000223960 Plasmodium falciparum Species 0.000 description 3
- 229960002970 artemotil Drugs 0.000 description 3
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 description 3
- 229940000425 combination drug Drugs 0.000 description 3
- 229960001404 quinidine Drugs 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- 208000009182 Parasitemia Diseases 0.000 description 2
- 241000223810 Plasmodium vivax Species 0.000 description 2
- 206010035503 Plasmodium vivax infection Diseases 0.000 description 2
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 2
- 229960000611 pyrimethamine Drugs 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 1
- 206010053172 Fatal outcomes Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 241001505293 Plasmodium ovale Species 0.000 description 1
- 206010035502 Plasmodium ovale infection Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 description 1
- 229960003159 atovaquone Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229930009674 sesquiterpene lactone Natural products 0.000 description 1
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 229960004673 sulfadoxine Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
d . NE
AaNTIMALARIAL COMPOSITIONS AND PROCESS THEIRFEOF
Technical Field 5 .
The present invesntion relates to pharmaceutical combinations comprising antimalarial compositions such as artemisinin, quinoline and their derivatives. Im particular, the present in—vention is concerned with pharmacetiatical formulations comprising combinations of artemisinin, quinoline and their derivatives, usefful particularly in the prophylaxis and. treatment of protozoal infZections; particularly, malaria.
Background anzd Prior art
Human malariae is caused by four species of obligate intracellular proteozoa of the genus
Plasmodium.
Malaria, caused by four species of Plasmodium, of which Plasmodium falc=iparum is the most dangerous, remains the world’s most devastating hum an parasitic infection. :
Each Plasmodii=m species causes a characteristic illness and shows distinguishing morphological features in blood smears: (1) P. falciparum causes rmalignant tertian malaria, the most dangerous form of human rmalaria. By invading erythrocytes of any age, this species can produce a devastating parasitemia, se:questration of infected erythrocsstes, in the peripheral microvasculature, hypoglycemia, Imemolysis, and shock with multiorgan failure. Delay in the treatment until after demonstration of parasitemia may lead to a fatal outcome even after the periph eral blood is free of parasites. If treatzed early, the infection usually respory.ds within 48 hours to app—ropriate therapy. (2) P. vivax causes benign tertian malaria. (3) P. ovale causes a rare malarial infection with a periodicity and rezlapses similar to those of P. vivax, brat is milder.
Antimalarials ca_n be categorized by the stage of the parasite that they affesct and the clinical indication for th eir use. Some drugs have more thara one type of antimalarial activity. Nearly all antimalarial druggs were developed because of their action against asexual er—ythrocytic forms of d malarial parasimes that cause clinical illness. Efficacious, rapidly acting drugs in this category include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisimnin compounds.
Yet, due to the =continuing spread of increasingly drug-resistant and multidrug-resist-ant strains of P. falciparum, no ssingle agent successfully controls infections with these parasites. Instead, use of two or more antimalarial agents with complementary properties is recommended.
Artemisinin is =a sesquiterpene lactone endoperoxide derived from the weed ging hao (Artemisia annua), also called sweet wormwood or annual wormwood. Chinese scientists haed extracted and crystallized the major antimalarial ingredient, girzghaosu, now known as artesmisinin. They synthesized threse derivatives with greater antimalarial potency than artemisinin itself namely, dikydroartemisiarin, artemether and artesunate, the water-soluble hemisuccinate salt of dihydroartemisirin.
Artemisinin con—apounds are the most rapidly acting, effective and safe drugs for tlhe treatment of severe malaria, including infections due to chloroquine and multidrug-resistant= strains of P.
Jalciparum. Although artemisinin and its derivatives can be used as single agents, infections can often relapse.
Hence, the present invention relates to a combination of antimalarial agents and mcore specifically permits desirable antimalarial therapy while preventing or delaying the development cf resistance.
The use of comtoinations of different antimalarials is known in malarial chemotherapy. In the prior art, various comtoination antimalarials are reported for delaying the development of ressistance.
US patent no. 5,219,865 describes combination therapy of artesunate with guanine and its derivatives. Thes patent relates to combinations of the malaria therapeutics artemisinine, dihydroartemisin ine, arteether, artemether, artesunate or other artemisinine derivatives with one or more of the antimalarial chloroquine, 10-o-methylfloxacrine, quinine, mefloquine, amodiaquine, pyrimethamine, sulfadoxine and primaquine but there is not sufficient dissclosure’ of a pharmaceutical p=roduct/composition of the said composition by way of any example cor process.
“EP patent no. 0,362,810 describes combination therapy of arte sunate with quinidine aned its derivatives. This patent relates to a new and improved antimalaria”l composition and a method of
Ereating malaria which employs a combination with, on the one hand, one of the antimalarial agents artemisinine, dihydroartemisinine, arteether, artemether, artesunate a nd on the other hand, quinidine end optionally mefloquine and their pharmaceutically acceptable saltss.
A\ combination of Amodiaquine and tetracycline and a combirnation of Pyrimethamine and
Sulphadoxine has already been used in treatment of P. falciparum nmalaria in Thiland. (Reporte=d in « Tropical Diseases Research, seventh programme report” Chapter-2; malaria, published by WHO).
I= has now been found, surprisingly, that combinations of artemisin in and/or its above mentio-ned d erivatives with the known malaria therapeutics like chloroquine, me=floquine, amodiaquine and the pharmaceutically utilizable salts thereof show a synergistic action.
TThe present combination of antimalarials which is described in mores detail hereinafter permits the dessired malaria treatment, specifically both for prophylaxis and for tlmerapy, and prevents or del ays thee development of resistance.
W~ e are unaware of any pharmaceutical composition of the combinatiomn of the present invention ams a fixed dose combination (two drugs combined in one tablet). The co-ampositions being sold to d_ate ar-e in the form of kits wherein each drug has to be taken as a separate mablet.
Owbhjectives
Thue object of the present invention is to provide a pharmaceutical preoduct comprising at least o-ne art=emisinin or its salts or derivatives thereof and at least one quinol—ine or its salts or derivatives thereof, preferably a chloroguinoline, or its salts or derivatives therecsf as a combined preparation, for= simultaneous or separate use in the treatment of malaria.
’ ( . 4 :
Accordingly, it is an object of the present invention to provides fixed dose combinatiorz of antimal=arial agents which specifically” permits antimalarial therapy winile preventing or delayings the developmment of resistance.
It is another object of the present invention to provide a process for {hme manufacture of a fixed dose combina tion comprising at least one artemisinin or its salts or derivamtives thereof and at least one quinoline or its salts or derivatives thereof as a combined preparatior in suitable pharmaceutically acceptab le carriers.
Summar—y of the invention
The press=ent invention provides a pharamaceutical product comprising «at least one artemisinin or its salts or d_erivatives thereof and at least one quinoline or its salts or deri~vatives thereof as a combired preparaticon, for simultaneous or separate use in the treatment of malaria.
It will bes appreciated from the abovre, that the respective therapeumtic agents of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical formulatieons or separately. If there is separate administration, it will also be appreciated that the subsequerntly administered therapeutic z2gents should be administered tow 2 patient within a time scale so as to achieve, or more particularly optimize, the above referred to advantageous synergistic therapeut® c effect of a combined preparation as present in a pharmaceut=ical product according to tThe present in~vention.
Also com pliance to the treatment is crucial to ensure treatment effectiveness and prevent futuzre resistance. When combination is provid ed as two separate drugs, patients might take only one of tiae two drugs or fail to complete the whole course. The protection against resistance is also lost if ore drug is t aken without the other. To optimize the patient compliance it is therefore very advantageous to provide patients with fixed dose combinations rather thaan separate tablets.
[ .
Also, according to the present invention, there is proviced a pharmaceutical form: ulation comprising at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivatives thereof, for™ use in the treatment of malaria, together with a pharmace=utically acceptable carrier or excipient themeof.
S
Also, according to the present invention, there is provicled the use of at least one artemisinin or its salts or derivatives thereof and at least one quinoline or its salts or derivativ—es thereof, in the manufacture of a mediczament for use in the treatment of malaria.
In the pharmaceutical poroducts or formulations accordieag to the present inventiozn, artemisinin and derivatives suitably incsludes dihydroartemisinin, arteet her, artemether, and artessunate, the water- soluble hemisuccinate ssalt of dihydroartemisinin or a poharmaceutically acceptable salt, solvate or physiologically functioral derivative thereof. Preferably. the derivative employed according to the present invention is arte-sunate.
Artesnnate is the water—soluble hemisuccinate salt of dilnydroartemisinin, namely, Butanedioic acid mono-[3R,5aS, 6R,8aS_9R,10R,12R,12aR)-decahydro-3 ,6,9-trimethyl-3,12-epoxy—12H-pyrano(4,3- j]-1,2-benzodioxepin-10=-yl] ester. As mentioned above a pharmaceutically accep=table salt thereof may be used.
Artesunate, semi-synthestic derivative of artemisinin, h=as been used in the treat—ment of malaria.
Artesunate is active in typical blood schizonticides in all forms of malaria. It has a peroxide bond, which breaks up inside “the parasite, forming singlet oxs/gen as well as free radic-als. Both exert a direct cytotoxic effect omn the cells, which forms the esssential part of the mecharmism of action of artesunate and explains ists rapid effect as well as its efficamcy.
Following oral administaration, artesunate is rapidly absorbed and reaches Cmax within 45 to 90 minutes. The product is metabolized in the liver by hycrolysis, giving rise to diRaydroartemisinin which is also effective a_gainst malaria by the same mec hanism of action. Elimination half-life of the drug is approximately~ 2 to 4 hours.
Claims (31)
- L. A pharmaceutical stable product comprising (i) at least one artemisini—m or a salt or derivative thereof, and a® least one quinoline or a salt or derivative thereof, =ms a combined preparation, for simultaneosus or separate use in the treatmen t of malaria.
- 2. A pharmaceutical feormulation comprising (i) at least one artemisinin or a sa-1t or derivative thereof, and at least one qtyinoline or a salt or derivative th-ereof, together with a plmarmaceutically acceptable carrier or excipieent thereof.
- 3. A pharmaceutical product according to claim 1, or a pharmaceutical formulamtion according to claim 2, wherein said artemisinin is selected from the group consisting of arter—nisinin per se, dihydroartemisinin, artesthesr, artemether, and artesumate, fae water-soluble hemisu .ccinate salt of dihydroartemisinin or a pliarmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
- 4. A product or formulation according to claim 3, wherein said artemisinin derivative is artesunate.
- 5. A pharmaceutical product or formulation according to any one of claims 1 to 4 , wherein said quinoline is selected from the group consisting of chloroquine, mefloquine, amodiaquine, and primaquine or a pharmaceutically acceptable salt, solvate or- physiologically functiomnal derivative thereof.
- 6. A pharmaceutical product or formulation according to claim 5, wherein said quinoline is amodiaquine, preferably amomdiaquine hydrochloride.
- 7. A pharmaceutical product or formulation according~ any one of claims 1 to 6, which comprises an oral drug delive=ry form which may be a tablet or a capsule.
- © 8. A pharmaceutical product or formulation according to claim 7, wherein said deslivery form is tablet, preferabl=y a bilayer tablet.
- 9. A pharmaceutical product or formulation according to any one of claims &5 to 8, which comprises a bilayer system comprising a first layer comprising at least one artemisin in or a salt or derivative thereof and a second layer comprising at least one quinoline or a salt or derivative thereof.
- 10. A pharmmaceutical product or formulation according to claim 9, wherein the first layer comprises substantially 5 to 50 % artemisinin or its salts or derivatives, substantiall—y 50 to 90 % binder/diluents, substantially 2 to 10% disintegrant and substantially 0.2 to 2 % of a Iuloricant.
- 11. A pharm aceutical product or formulation according to claim 10, wherein the first layer comprises substantially 5 to 50% of artesunate, substantially 50 to 90 % lactose, substantially 2 to 10% croscarmelleose sodium and substantially 0.2 to 2 % of a lubricant.
- 12. A pharmaceutical product or formulation according to claim 10, wherein the tinder and/or diluent are selectesd from lactose and microcrystalline celthalose.
- 13. A pharmaceutical product or formulation according to any one of claims 9 to 12, wherein the second layemr comprises substantially 35 to 85 % quinoline or its salts or derivatives, substantially 5 to 40 % binder/diluent, substantially 1 to 10 % disintegrant and substantially 0.2 to 2 % of a lubricant.
- 14. A pharma ceutical product or formulation according to claim 13, wherein the second layer comprises substartially 35 to 85 % of amodiaquine hydrochloride, substantially 5 to 4CO % starch or microcrystalline cellulose, substantially 1 to 10 % pregelatinized starch or sodium starch glycollate and substantially O.2 to 2 % of a lubricant.
- 15. A pharmaceutical product or formulation according to claim 13, wherein the bi_nder/diluent is selected from stzarch, lactose, dicalcium phosphate, mannitol and microcrystalline cellt_alose.
- 16. A pharmaceutical product or formulation according to claim 10 or 13, wherein the disintegrant is selected from microcrystallines cellulose, sodium starch glycollate, starch, croscarmelloses sodium and hydroxypropyl cellulose. :
- 17. A pharmaceutical product or formulation aaccording to claim 10 or 13 , wherein the lubricant is selected from talc, fatty acids, and salts of fatty acids, mineral oil, colloidal silicon dioxide and hydrogenated ~vegetable oils.
- 18. A pharmaceutical product or formulation according to any one of cMaims 9 to 17, wherein the bilayer tablet is coated.
- 19. A procsess for preparing a pharmaceutical yoroduct or formulation according to any preceding claim, comprising (a) precompressing a first layer comprising at least one ar-temisinin or its salts or derivatives followed by compressing with the pr ecompressed layer (b) a se=cond layer comprising granules of at least one quinoline or its salts or derivatives along with (a).
- 20. A proecess according to claim 19, wherein the first layer compri ses artesunate, and is prepared by lending artesunate with diluents and binders, disintegrants, glidants, lubricant and compressing tThe resulting mixture. ’
- 21. A process according to claim 19 or 20, winerein the second layer comprises a quinoline, such as amodiaquirae, and is prepared by wet granulating amodiaquine with suitable excipients.
- 22. A pro cess according to claim 19, wherein the two layers are prespared by using direct compression Of Wet granulation or dry granulatiors processes. :
- 23. A pharmaceutical product or formulation =ccording to claim 7, where=in said delivery form is capsule,
- 24. A pharmaceutical paroduct or formulation according te claim 23, wherein the =capsule comprises at least one artermisinin or a salt or derivative thereof, and at least one quinoline ©r a salt or derivative thereof, together with a pharmaceutically carrier or esxcipient thereof.
- 15. A process for preparing a pharmaceutical product or fomulation according to clamim 24, which process comprises gramnulating the or each artemisinin or its salt or derivative, and the wor each quinoline or its salt or deriva tive separately and then filling in caprsules.
- 2%. A process according to claim 25, wherein the granules of= the or each artemisinin or its salt or derivative is obtained by dry granulating the said artemisinira along with suitable diluerats and lubricants to form slugs whicsh are then subjecting to milling.
- 27. A process according ~to claim 25 or 26, wherein the grantales of the or each quinoline or its salt or derivative is obtained “by wet granulating the said quinoline with suitable excipients.
- 28. A method of treating a disease in a subject in need of tresatment, which method comprises administering to the subject a pharmaceutical product or formulati on according to any of clairmas 1 to 18, 23 or 24.
- 29, A method according t-o claim 28, wherein the disease is ma laria.
- 30. A pharmaceutical composition comprising a therapeuticall y effective amount of at lea_st one =rtemisinin or a salt or derivative thereof, and at least one quinoline or a salt or derivative thmereof, ~for uge in the treatment of ma laria, together with a pharmaceutically acceptable carrier or excipoient.
- 31 Use of at least one artzemisinin or a salt or derivative thereof, and at least one quinolin_e or a salt or derivative thereof, in the manufacture of a medicament for tthe treatment of malaria.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN902MU2003 | 2003-09-04 |
Publications (1)
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| ZA200602031B true ZA200602031B (en) | 2007-05-30 |
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| ZA200602031A ZA200602031B (en) | 2003-09-04 | 2004-09-03 | Antimalarial compositions and process thereof |
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| BR (1) | BRPI0413767A (en) |
| WO (1) | WO2005023304A2 (en) |
| ZA (1) | ZA200602031B (en) |
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| BRPI0401107A (en) * | 2004-04-13 | 2005-11-22 | Fundacao Oswaldo Cruz | Compounds derived from artesunate, process of preparing these compounds, pharmaceutical composition containing said compounds, use of the respective medicine in the treatment or prevention of malaria or other parasitic diseases and therapeutic method |
| FR2884715B1 (en) * | 2005-04-20 | 2007-06-15 | Sanofi Aventis Sa | ASSOCIATION BETWEEN FERROQUIN AND AN ARTEMISININE DERIVATIVE FOR THE TREATMENT OF MALARIA |
| WO2007036947A1 (en) * | 2005-09-30 | 2007-04-05 | Ipca Laboratories Limited | Delayed release anti-malarial composition |
| WO2007043061A1 (en) * | 2005-10-11 | 2007-04-19 | Ipca Laboratories Ltd. | Anti-malarial combination and methods of formulation |
| CH696229A5 (en) * | 2006-05-13 | 2007-02-28 | Professeur Dr Achille Benakis | Antimalarial composition in geometrical solid tablet form obtained by the compression of a medicine powder and excipients, useful to treat malaria, comprises three separate layers |
| FR2914860B1 (en) * | 2007-04-12 | 2009-05-22 | Ile D Inventeurs Apis Spheromo | MULTILAYER SPHEROIDS WITH ANTIPALUDITIC ACTION IN WHICH ONE OF THE LAYERS CONTAINS ARTESUNATE |
| CN101756982B (en) * | 2008-12-17 | 2012-07-04 | 重庆医药工业研究院有限责任公司 | Artesunate compound medicine composition with improved mouth feeling and high stability |
| FR2951945B1 (en) * | 2009-11-05 | 2013-08-09 | Sanofi Aventis | PHARMACEUTICAL COMPOSITION |
| WO2015041722A1 (en) * | 2013-09-17 | 2015-03-26 | Kryptonite Group, Ltd | Enhanced artemisinin-based combination therapy for treating parasitic mediated disease |
| TWI733649B (en) * | 2014-03-07 | 2021-07-21 | 巴哈馬商克利普頓集團公司 | Enhanced artemisinin-based combination therapy for treating parasitic mediated disease |
| US20170326102A1 (en) * | 2014-11-27 | 2017-11-16 | Cipla Limited | Pharmaceutical Composition Comprising an Artemisinin Derivative for Nasal or Pulmonary Delivery |
| CN107982227A (en) * | 2017-12-05 | 2018-05-04 | 昆药集团股份有限公司 | A kind of tablet of dihydroartemisinine and preparation method thereof |
| CN107982228B (en) * | 2017-12-05 | 2022-08-16 | 昆药集团股份有限公司 | Dihydroartemisinin tablet and preparation method thereof |
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| US3019169A (en) * | 1958-06-23 | 1962-01-30 | Sterling Drug Inc | Salicylate dry shell coating of dry 4-aminoquinoline core, and dry-compressing tablet-making process |
| US5219865A (en) * | 1987-05-08 | 1993-06-15 | Hoechst Aktiengesellschaft | Pharmaceutical combination for the prophylaxis and therapy of malaria |
| DE68906345T2 (en) * | 1988-10-07 | 1993-10-28 | Hoechst Ag | Antimalarial compositions utilizing quinidine, artemisinin and their derivatives. |
| CN1058717A (en) * | 1990-08-08 | 1992-02-19 | 中国人民解放军军事医学科学院微生物流行病研究所 | New antimalarial agent-Coartem and preparation method thereof |
| DE60229440D1 (en) * | 2002-02-13 | 2008-11-27 | Mepha Ltd | COMPOSITION OF ARTHROUSATE AND MEQUOQUIN FOR THE TREATMENT OF MALARIA |
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- 2004-09-03 ZA ZA200602031A patent/ZA200602031B/en unknown
- 2004-09-03 WO PCT/GB2004/003748 patent/WO2005023304A2/en active Application Filing
- 2004-09-03 BR BRPI0413767-1A patent/BRPI0413767A/en not_active Application Discontinuation
- 2004-09-03 AP AP2006003557A patent/AP2006003557A0/en unknown
Also Published As
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| AP2006003557A0 (en) | 2006-04-30 |
| WO2005023304A3 (en) | 2005-07-07 |
| WO2005023304A2 (en) | 2005-03-17 |
| BRPI0413767A (en) | 2006-10-31 |
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